This application explores a novel role for the carotid bodies in whole body glucose homeostasis in humans. The carotid bodies sense arterial oxygen tension and regulate ventilation. However, studies in isolated carotid body cells and animal models indicate these receptors also sense changes in blood glucose and that changes in the partial pressure of oxygen (pO2) alter this sensitivity. There is also evidence in humans suggesting that changes in arterial pO2 influence blood glucose homeostasis, but the role of the carotid bodies in regulating blood glucose is essentially unexplored in humans. To address the role of the carotid bodies in human glucose homeostasis we will systematically manipulate arterial pO2 and measure the counterregulatory responses to hypoglycemia in three groups of subjects: 1) healthy people, 2) people with bilateral carotid denervation after surgery for glomus tumors, and 3) people with type 1 diabetes with and without hypoglycemia unawareness. In this context, we will address the following specific aims: Aim 1) tests hypotheses related to how arterial pO2 influences counterregulatory responses to hypoglycemia in healthy subjects. We will perform hyperinsulinemic hypoglycemic clamps during normoxia, hyperoxia, and hypoxia maneuvers that should suppress (hyperoxia) or enhance (hypoxia) the ability of the carotid bodies to sense hypoglycemia and alter counterregulatory responses to hypoglycemia. These studies will be conducted in normal subjects. Aim 2) tests hypotheses related to how surgical resection of the carotid bodies alters counterregulatory responses to hypoglycemia. We will compare physiological responses to hyperinsulinemic hypoglycemic clamps in subjects who have undergone bilateral carotid body denervation for the treatment of glomus tumors with controls. Aim 3) tests hypotheses related to the idea that carotid body dysfunction in people with Type 1 diabetes is associated with hypoglycemia unawareness. We will measure hypoxic ventilatory responses and perform hypoglycemic clamps during normoxia, and hypoxia in people with type 1 diabetes with and without hypoglycemia unawareness. The idea is that failure of the carotid bodies to sense and initiate responses to hypoglycemia contributes to hypoglycemia unawareness. Summary: To our knowledge this is the first effort to systematically test the role of the carotid bodies in human whole body glucose homeostasis-ideas based on provocative data from a limited number of studies in isolated cells and animal models. In this context, we have proposed a suite of novel aims and hypotheses and linked ideas on basic mechanisms to a biomedically significant pathophysiological condition (hypoglycemia unawareness) in type 1 diabetes. Our ideas about the carotid bodies as sensors of both hypoxia and hypoglycemia also have implications for conditions linked to hypoxia such as sleep apnea which is also associated with type II diabetes. Finally, our overall goal, aims and hypotheses are aligned with the new NIH review criteria that emphasize innovation, impact and significance; and our team has the expertise to successfully execute the novel experiments we are proposing.